Skeletal remodeling is characterized by an intercellular communicating network between osteoclastic and osteoblastic precursors and more differentiated bone forming osteoblast and the bone resorbing osteoclast, all of which is controlled by a complex interaction with bone matrix proteins and a paracrine-endocrine-autocrine interplay between local and systemic osteotrophic factors. This multidisciplinary research program will apply the techniques and concepts of cell and molecular biology to analyze cellular models of biological responses to osteotrophic factors, and to pursue the role of cell-cell and cell-matrix interactions in the transduction of these responses. In order to achieve these goals we propose to: (i) analyze the relationships between integrins-matrix protein interactions to the growth and differentiation of osteoblasts and the effects of cytokines and growth factors thereon; and to identify pivotal signal transduction pathways which mediate the interactions between integrins, matrix proteins and osteoblast function; (ii) analyze the role of metalloproteinases and matrix cleavage in osteoclast activation with the goals of identifying the structural requirements for activation, characterizing the osteoclast receptors necessary for activation, and determining the role of vacuolar H+ATPase polarization in the osteoclastic and osteoblastic activity response; (iii) analyze the role of integrins in response to mechanical strain as they participate in the generation of anabolic signals and cytoskeletal changes in the human osteoblast; (iv) to define a profile of osteoclast-derived chemokines and to analyze hormonal, cytokine and matrix-dependent modulation of osteoblast development, migration and function; and (v) to identify and characterize the chemokine receptors on osteoblasts as a function of osteoblast differentiation and activity. A specialized resource center designated as the "Cell Biology Core Laboratory" will provide assistance and consultation in experimental designs, preparation of appropriate cell cultures, immunochemistry,, ELISAs for cytokines, technical support for in situ hybridization analyses, and a centralized repository for cDNA probes.